1-(Aminoalkylphenyl and aminoalkylbenzyl)-indoles and indolines

ABSTRACT

The invention relates to 1-(aminoalkylphenyl and aminoalkylbenzyl)indoles and indolines of the formula: ##STR1## where R 1  and R 2  are the same or different and are hydrogen, lower alkyl, cycloalkyl and acyl of the formula ##STR2## where R 3  is lower alkyl, lower alkoxy, cycloalkyl, phenyl of the formula ##STR3## and Ar lower alkyl of the formula -lower alkylene ##STR4## X is hydrogen, halogen, lower alkoxy, Ar lower alkoxy of the formula ##STR5## lower alkylene --O--; m and p are independently integers of 0 and 1 and the pharmaceutically acceptable acid addition salts thereof.

This is a division of application Ser. No. 562,301 filed Dec. 16, 1983,now abandoned which is in turn a division of Ser. No. 367,707 filed4-12-82 now U.S. Pat. No. 4,448,784.

To the best of our knowledge the compounds of the present invention havenot heretofore been described or suggested.

The compounds of the present invention have the general formula ##STR6##where R₁ and R₂ are the same or different and are hydrogen, lower alkyl,cycloalkyl and acyl of the formula ##STR7## where R₃ is lower alkyl,lower alkoxy, cycloalkyl, phenyl of the formula ##STR8## and Ar loweralkyl of the formula -lower alkylene ##STR9## X is hydrogen, halogen,lower alkoxy, Ar lower alkoxy, of the formula ##STR10## m and p areindependently an integer of 0 or 1 and the pharmaceutically acceptableacid addition salts thereof.

In the above definitions the term "lower" means the group it isdescribing contains from 1 to 6 carbon atoms. The term "alkyl" refers toa straight or branched chain hydrocarbon containing no unsaturation,e.g. methyl, ethyl, isopropyl, 2-butyl, neopentyl, n-hexyl, etc.; theterm "alkoxy" refers to a monovalent substituent which consists of analkyl group linked through an ether oxygen having its free valence bondfrom the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy,etc.; the term "cycloalkyl" refers to a monovalent substituentconsisting of a saturated hydrocarbon group possessing at least onecarbocyclic ring, of 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc., having its free valence bondfrom a carbon of the carbocyclic ring; the term "Ar lower alkyl" refersto a monovalent substituent which consists of an aryl group, e.g.,phenyl, p-nitrophenyl, o-tolyl, m-methoxy phenyl etc. linked through alower alkylene group having its free valence bond from a carbon of thelower alkylene group, and having a formula of ##STR11## where X is aspreviously defined; the term "alkylene" refers to a bivalent radical ofthe lower branched or unbranched alkyl group it is derived from havingvalence bonds from two terminal carbons thereof, e.g. ethylene (--CH₂CH₂ --), propylene (--CH₂ CH₂ CH₂ --) isopropylene ##STR12## etc.; andthe term "halogen" refers to a member of the family consisting offluorine, chlorine, bromine and iodine.

The compounds of the present invention are prepared in the followingmanner. The substituents X, R₁, R₂ and R₃ and the integers m and p areas defined above unless indicated otherwise.

A. A substituted indoline or indole of the formula ##STR13## isselected. Compound (II) is reacted with a halobenzonitrile or a halotolunitrile having the formula ##STR14## (III) where Hal is a halogenselected from F, Cl, Br and I to form an intermediate of the invention##STR15## Compound IV is typically obtained by reacting compounds II andIII under nucleophilic substitution reaction conditions. Typically,where p=1, compound II is reacted with compound III in the presence of abase, e.g. NaH, (CH₃)₃ --C--OK, C₆ H₅ Li, and in a solvent, e.g.,dimethylsulfoxide (DMSO), dimethylformamide (DMF), xylene, etc. at atemperature of 0° to 200° C. for 1 to 24 hours to form compound IV.Alternatively, where p=0, compound II is reacted with compound III inthe presence of a base, e.g., K₂ CO₃, NaHCO₃, or even an excess of theindoline II serving as base, etc, without or with an inert solvent,e.g., chloroform, methylene chloride, toluene etc. at a temperature of-10° to 100° C. for 1 to 24 hours to form compound IV.

Compound IV in turn is reduced by conventional means, e.g. with a metalhydride such as LiAlH₄, BH₃ etc. in an inert solvent such astetrahydrofuran (THF), diethylether, dioxan, etc. at a temperature of-10° to 100° C. for 1 to 24 hours to reduce the cyano group to form acompound of the invention ##STR16##

B. Compound IV is hydrolyzed in a conventional manner utilizing eitheran acidic or alkaline medium whereby the cyano group is hydrolyzed to acarboxyl group to give an intermediate of the invention having theformula ##STR17## Compound VI is reduced by reaction with a metalhydride, e.g. LiAlH₄, BH₃, AlH₃, etc., in an inert solvent, e.g. THF,ether, dioxan, etc, typically at a temperature of -10° to 100° C. for 1to 24 hours to form an alcohol intermediate of the invention having theformula ##STR18## Compound VII is, in turn, reacted with a sulfonylhalide of the formula R₄ SO₂ --Hal (VIII) where Hal is a halogenselected from F, Cl, Br and I, and R₄ is lower alkyl, e.g. methyl, oraryl such as phenyl or tolyl, to form a sulfonate intermediate of theinvention having the formula ##STR19## where R₄ is lower alkyl, e.g.methyl, or phenyl. Typically compound VII is reacted with compound VIIIin an inert solvent, e.g. dichloromethane, ether, etc. at a temperatureof 0° to 100° C. for 1 to 24 hours to form compound IX. Compound IX isthen reacted with an inorganic cyanide, e.g. NaCN, KCN, in aconventional manner in the presence of a solvent, typically an aproticpolar solvent such as methanol, ethanol, dimethyl formamide (DMF),N-methyl-2-pyrrolidone or dimethyl sulfoxide (DMSO), to form anintermediate of the invention having the formula ##STR20## The cyanogroup of compound X is reduced in the manner previously described toform a compound of the invention having the formula ##STR21##

C. Compound IV is reacted in a conventional manner with a Grignardreagent of the formula R₅ MgHal, (XII) where Hal is a halogen selectedfrom Cl, Br and I and R₅ is an alkyl group of 1 to 5 carbon atoms, orphenyl to form an intermediate of the invention having the formula##STR22## Typically, compound IV is reacted with the Grignard reagent(XII) in an inert solvent, e.g. tetrahydrofuran (THF), ether, dioxanetc., at a temperature of 0° to 100° C. for 1 to 24 hours to formcompound XIII. Compound XIII is then reduced by reduction with metalhalide, e.g. LiAlH₄, as previously described for the reduction of thecyano group, to form a compound of the invention having the formula##STR23##

D. The N-alkyl or N-acyl derivatives of compounds V, XI and XIV areprepared in a conventional manner, as for example by reaction with alower alkyl halide or a cycloalkyl halide or an acylhalide of theformula ##STR24## where Hal is a halogen selected from F, Cl, Br and Iand R₃ is as previously defined, whereby a mono- or bi-substitutedcompound of the invention, Compound I, is obtained where at least R₁ orR₂ is lower alkyl, cycloalkyl or acyl of the formula ##STR25##Alternatively, compounds V, XI and XIV can be reacted in a conventionalmanner with an alkylchloroformate followed by reduction of the resultantcompound, as with LiAlH₄, NaBH₄, to form compound I of the inventionwhere at least R₁ or R₂ is methyl. In another alternative embodiment,compounds V, XI and XIV can be reacted in a conventional manner with anacid anhydride, ##STR26## to form compound I of the invention where atleast R₁ or R₂ is lower alkyl.

E. Where p is 1 in compound IV, it is typically reduced to compound IVwhere p is 0 by reaction with sodium cyanoborohydride. Typically thisreaction is carried out in a solvent of THF, acetonitrile, or aceticacid at a temperature of 0° to 100° C. for 1 to 24 hours.

The compounds of the invention are useful as analgesic agents due totheir ability to alleviate pain in mammals. The activity of the compoundis demonstrated in the 2-phenyl-1,4-benzoquinone-induced writhing testin mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol. Med.,95, 729 (1975)]. The analgesic activity of some of the compoundsexpressed in terms of percent inhibition of writhing is given in TableI.

                  TABLE I                                                         ______________________________________                                                           Dose                                                                          (subcutaneous)                                                                            Inhibition                                                        mg/kg of body                                                                             Of writhing                                    Cmpound            Weight      %                                              ______________________________________                                        3-(1-indolinyl)benzene-                                                                          4.2         50                                             methanamine hydrochloride                                                     2-(1-indolinyl)benzene-                                                                          14.1        50                                             methanamine hydrochloride                                                     4-(1-indolinyl)benzene-                                                                          25.0        50                                             methanamine hydrochloride                                                     3-[5-chloro-1-indolinyl]benzene-                                                                 4.7         50                                             methanamine hydrochloride                                                     3-(1-indolyl)benzenemethanamine                                                                  19.1        50                                             hydrochloride                                                                 3-(5-chloro-1-indolinylmethyl)                                                                   20.2        50                                             benzenemethanamine fumarate                                                   N--cyclopropylcarbonyl-3-(1-                                                                     10.0        59.0                                           indolinyl)-benzenemethanamine                                                 N--cyclopropylmethyl-3-(1-                                                                       10.0        49.0                                           indolinyl)benzenemethanamine                                                  hydrochloride                                                                 N,N--dimethyl-3-(1-indolinyl)                                                                    25.0        50.0                                           benzenemethanamine hydrochloride                                              3-(1-indolinyl)-2-benzene                                                                        10.0        57.0                                           ethanamine.1/2 fumarate                                                       3-(1-indolinyl)-α-methylbenzene-                                                           10.0        40.0                                           methanamine hydrochloride                                                     propoxyphene       3.9         50                                             ______________________________________                                    

The analgesic relief of pain is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 1.0 to 25 mg/kgof body weight per day. A preferred effective dose within this range isfrom about 1 to 10 mg/kg of body weight per day. A particularlypreferred effective amount is about 5 mg/kg of body weight per day. Itis to be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need. Itis further to be understood that the dosages set forth herein areexamples only and that they do not, to any extent, limit the scope ofpractice of the invention.

Effective amount of the compounds of the present invention may beadministered to a subject by one of various methods, for example, orallyas in capsules or tablets, parenterally in the form of sterile solutionsor suspensions, and in some cases intravenously in the form of sterilesolutions. The compounds of the invention, while effective themselves,may be formulated and administered in the form of their pharmaceuticallyacceptable acid addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable acid addition salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, nitric, phosphoric, perchloric acids and the like as well asorganic acids such as tartaric, citric, acetic, succinic, maleic,fumaric acids and the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the 1-(aminoalkylphenyl) or1-(aminoalkyl benzyl)-indoles or indolines of the invention, the activeingredient, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of the compound present in such compositions is such that asuitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 5.0-300 milligrams of the1-(aminoalkylphenyl and aminoalkyl-benzyl)indoles and indolines of theinvention.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of the1-(aminoalkylphenyl and aminoalkylbenzyl) indoles and indolines of theinvention, but may be varied to be between 0.1 and about 50% of theweight thereof. The amount of the inventive compound present in suchcompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that a parenteral dosage unit contains between 5.0 to 100milligrams of the 1-(aminoalkylphenyl and aminoalkylbenzyl)indoles andindolines of the invention.

The solutions or suspensions may also include the following adjuvants: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein. All temperaturesare given in degrees centigrade.

EXAMPLE 1 a. 2-(1-Indolinyl)benzonitrile

A stirred mixture of 61.63 g (0.509 mole) 2-fluorobenzonitrile and 125.6ml (1.12 mole) indoline under nitrogen was heated at 170°-180° C. for22.5 hours. The resulting suspension was transferred to a separatoryfunnel with the aid of 400 ml of CH₂ Cl₂ and this solution was washedtwice with water (400 ml), four times with 4N HCl (450 ml), water (450ml), brine (400 ml), dried (Na₂ SO₄), and concentrated to give 78.6 g(71.5%) of a liquid. The crystals which formed on standing werefiltered, washed with ether and dried at 42° C. under vacuum, thusaffording 4.33 g (3.9% overall) of 2-(indolinyl)benzonitrile M.P.94.0°-96.5° C.

ANALYSIS: Calculated for C₁₅ H₁₂ N₂ : 81.79%C; 5.49%H; 12.72%N; Found:81.60%C; 5.54%H; 12.65%N

b. 2-(1-Indolinyl)benzenemethanamine hydrochloride

A solution of 17.18 g (0.078 mole) of 2(1-indolinyl)benzonitrile ofExample 1a in 150 ml dry tetrahydrofuran (THF) was added dropwise to arapidly stirred ice cold solution of BH₃ in THF (236 ml of 1M solution;0.236 mole) under nitrogen. At the end of the addition the resultantsolution was permitted to warm to room temperature and stir for 3 hoursand then heated at reflux for 50 minutes. The product was then cooled to0° C., treated dropwise with 6N HCl (100 ml), and permitted to standovernight (about 16 hours) at room temperature. The reaction mixture wascooled to 0° C. and made basic using solid NaOH. The resulting aqueouslayer was extracted with ether (200 ml) and the combined organicportions were washed twice with brine (200 ml portions), dried over K₂CO₃, and concentrated to afford 21.1 g of crude free base. The freeamine was dissolved in dry ether (300 ml), cooled to 0° C., and treatedwith gaseous HCl. The resulting salt was filtered, washed with dry ether(300 ml), and dried under vacuum at 40° C. thus affording 19.25 g(94.4%) of crude salt, m.p. 226°-228° C. Recrystallization of 15.59 g ofthe crude salt from methanol-ether afforded 10.49 g (67.3% recovery) of2-(1-indolinyl) benzenemethanamine hydrochloride, m.p. 231°-232° C.

ANALYSIS: Calculated for C₁₅ H₁₆ N₂.HCl: 69.09%C; 6.57%H; 10.74%N;Found: 68.85%C; 6.57%H; 10.64%N

EXAMPLE 2 a. 4-(1-Indolinyl)benzonitrile

4.94 g (0.206 mole) 99% NaH was added in one portion to a solution of21.6 ml (0.188 mole) indoline in 85 ml sieve dried dimethylsulfoxide(DMSO) at room temperature. The resulting slurry was permitted to stirat room temperature for 2 hours and then cooled in an ice bath. Asolution of 25 g (0.206 moles) 2-fluorobenzonitrile in 35 ml DMSO wasadded dropwise. At the end of the addition, the ice bath was removed andthe mixture was permitted to stir at room temperature overnight (about16 hours). The product was poured onto 300 ml of ice and extracted withCHCl₃ (300 ml). The organic phase was thrice washed with water (500 mlportions), brine (500 ml), dried (Na₂ SO₄) and concentrated to give 39.9g (96.4%) of crude material. Two recrystallizations from isopropyl etherafforded 4-(1-indolinyl)benzonitrile, m.p. 88.5°-89.5° C.

ANALYSIS: Calculated for C₁₅ H₁₂ N₂ : 81.79%C; 5.49%H; 12.72%N; Found:81.60%C; 5.52%H; 12.72%N

b. 4-(1-Indolinyl)benzenemethanamine hydrochloride

A solution of 12.06 g (54.8 mmole) of 4-(1-indolinyl)benzonitrile ofExample 2a in 62 ml tetrahydrofuran (THF) was added dropwise to arapidly stirred ice cold solution of BH₃ in THF (181 ml of 0.93Msolution, 3.07 equiv. 168.4 mmole) under nitrogen. After heating atreflux for 1.5 hours, the solution was permitted to cool to roomtemperature and stand overnight. The ice cold reaction mixture was thentreated dropwise with 6M aq. HCl (100 ml), heated at reflux for 40minutes, cooled to 0° C., and made basic using solid NaOH. The resultingaqueous phase was extracted with ether and the combined organic portions(100 ml total) were washed with water (300 ml), twice with brine (300 mlportions) dried (Na₂ SO₄) and concentrated to afford 13.2 g of crudefree base. A solution of 7.5 g (33.4 mmole) of crude free base in 200 ml1:1 ethanol-ether was treated with 50 ml of ethanolic HCl. 200 ml dryether was added and the resulting solid was filtered, washed with dryether, and dried thus giving 5.9 g (67.7%) of crude product.Recrystallization from hot ethanol-ether (charcoal) afforded 2.98 g ofpure 4-(1-indolinyl)benzenemethanamine hydrochloride, m.p. 251.5°-252.5°C.

ANALYSIS: Calculated for C₁₅ H₁₆ N₂.HCl: 69.09%C; 6.57%H; 10.74%N;Found: 69.02%C; 6.60%H; 10.66%N

EXAMPLE 3 a. 3-(1-Indolinyl)benzonitrile

4.63 g (0.0193 mole, 1.1 equiv.) 99% NaH was added in one portion to astirred solution of 19.8 ml (0.175 mole) indoline in 90 ml sieve driedDMSO under nitrogen at room temperature. After 65 minutes, the mixturewas cooled in an ice bath and treated dropwise with a solution of 23.43g (0.193 mole, 1.1 equiv.) 3-fluorobenzonitrile in 34 ml dry DMSO. Theproduct was permitted to stir overnight at room temperature, poured onto300 ml ice and extracted with CHCl₃. The organic layer was washed fivetimes with water (800 ml portions), dried over MgSO₄, and concentratedto give 42.75 g (38.6 g theory) of oil. 2.0 g of the crude product waschromatographed on silica gel (104 g) using ether-hexane thus affordinga 0.99 g sample of an oil of pure 3-(1-indolinyl)benzonitrile.

ANALYSIS: Calculated for C₁₅ H₁₂ N₂ : 81.79%C; 5.49%H; 12.72%N; Found:81.76%C; 5.37%H; 12.59%N

b. 3-(1-Indolinyl)benzenemethanamine hydrochloride

A solution of 7.1 g (32.3 mmole) of 3-(1-indolinyl)benzonitrile ofExample 3a in 44 ml THF was added dropwise over 30 minutes to an icecold solution of 129 ml (129 mmole, 4 equivalents) of 1M BH₃.THF complexunder nitrogen. After heating at reflux for 1 hour, the reaction mixturewas cooled to 0°-5° C. and treated dropwise with 50 ml concentrated HCl.The resulting suspension was heated at reflux for 1 hour, permitted tostand at room temperature overnight (about 16 hours) and then made basicusing 50% NaOH (60 ml). The reaction mixture was partitioned betweenwater-CH₂ Cl₂ (300 ml each) and the organic phase was washed with brine(300 ml), dried over MgSO₄ and concentrated to give 8.9 g of crude freebase. Conversion as in Example 1 to the HCl salt (ethanol/ethereal HCl)and recrystallization from hot acetonitrile-methanol afforded 2.86 g(34% overall) of 3-(1-indolinyl)benzenemethanamine hydrochloride, m.p.170.5°-173.5° C.

ANALYSIS: Calculated for C₁₅ H₁₆ N₂.HCl: 69.09%C; 6.57%H; 10.74%N;Found: 69.13%C; 6.64%H; 10.78%N

EXAMPLE 4 a. 3-(5-Chloro-1-indolinyl)benzonitrile

A slurry of 2.64 g (0.11 mole, 1.1 equivalents) sodium hydride in 15.36g (0.1 mole) 5-chloroindoline and 50 ml sieve dried DMSO was permittedto stir at room temperature under nitrogen for 2 hours. While cooling inan ice bath, a solution of 12.11 g (0.1 mole) 3-fluorobenzonitrile in 15ml sieve dried DMSO was then added dropwise over 15 minutes. AT the endof the addition, the ice bath was removed and the reaction mixture waspermitted to warm to room temperature and stir overnight (20 hours). Theproduct was poured onto ice and then extracted twice with CHCl₃. Thecombined organic portions (400 ml) were washed four times with water(400 ml portions), 4N HCl (three 300 ml portions) brine (300 ml), driedover Na₂ SO₄, and concentrated to give 28.03 g (25.47 g theory) of asolid. Recrystallization from hot absolute ethanol containing 5-10%CHCl₃ afforded 11.12 g (43.66% overall) of3-(5-chloro-1-indolinyl)benzonitrile, m.p. 120°-121° C.

ANALYSIS: Calculated for C₁₅ H₁₁ ClN₂ : 70.73%C; 4.35%H; 13.92%Cl;11.00%N; Found: 70.46%C; 4.40%H; 14.07%Cl; 10.82%N

b. 3-(5-Chloro-1-indolinyl)benzenemethanamine hydrochloride

A solution of 10.66 g (41.85 mmole) of3-(5-chloro-1-indolinyl)benzonitrile of Example 4a in 100 ml dry THF wasadded dropwise to an ice cold rapidly stirred slurry of 6.35 g (167.4mmole, 4 equiv.) LiAlH₄ in 100 ml dry THF under nitrogen. After heatingat reflux for 2 hours, the reaction mixture was cooled in an ice bathand treated dropwise with 6 ml H₂ O, 6 ml 10% NaOH and 18 ml H₂ O. Theresulting salts were filtered and washed with hot CHCl₃. The filtratewas concentrated and the residue was dissolved in CHCl₃ (200 ml), washedwith brine (400 ml), dried over Na₂ SO₄, and concentrated to give 10.22g (94.4%) of free base. The resultant base was converted to the HCl salt(isopropanol-ethereal HCl) as in Example 1, and recrystallized from hotisopropanol-methanol to give 9.09 g (73.6% overall) of3-(5-chloro-1-indolinyl)benzenemethanamine hydrochloride, m.p. 220°-222°C.

ANALYSIS: Calculated for C₁₅ H₁₅ ClN₂.HCl: 61.03%C; 5.46%H; 9.49%N;Found: 61.26%C; 5.50%H; 9.47%N

EXAMPLE 5 a. α-(1-Indolinyl)-m-tolunitrile

An ice cold slurry of 10.6 g (76.9 mmole) K₂ CO₃ in 8.6 ml (76.9 mmole)indoline and 50 ml sieve dried dimethylformamide (DMF) was treateddropwise with a solution of 15 g (76.9 mmole) α-bromo-m-tolunitrile in75 ml sieve dried DMF. After stirring for 2 hours at room temperature,the reaction mixture was filtered and concentrated under high vacuum(55° C.). The residue was dissolved in CHCl₃ (150 ml) and washed twicewith water (250 ml portions), brine (250 ml), dried over Na₂ SO₄, andconcentrated to give 15.28 g (84.8%) of crude nitrile. Recrystallizationfrom hot ethanol gave 10.70 g (59.4% overall) of product, m.p. 54°-56°C. A second recrystallization of a 5.0 g sample afforded 2.74 g ofα-(1-indolinyl)-m-tolunitrile, m.p. 54.5°-56.0° C.

ANALYSIS: Calculated for C₁₆ H₁₄ N₂ : 82.02%C; 6.02%H; 11.96%N; Found:82.07%C; 5.96%H; 11.94%N

b. 3-(1-Indolinylmethyl)benzenemethanamine dihydrochloride

A solution of 13.09 g (55.87 mmole) of α-(1-indolinyl)-m-tolunitrile ofExample 5a in 120 ml distilled THF was added dropwise to a rapidlystirred ice cold slurry of 8.48 g (223.5 mmole, 4 equivalents) of LiAlH₄in 110 ml distilled THF. After heating at reflux for 18 hours, thereaction mixture was cooled to 0.5° C. and treated dropwise with 8.5 mlwater, 8.5 ml 10% NaOH, and 25.5 ml H₂ O. The salts were filtered,washed thrice with 100 ml hot CH₂ Cl₂, and the filtrate wasconcentrated. The residue was dissolved in CHCl₃ and washed with diluteaqueous NaOH, with brine, dried (Na₂ SO₄), and concentrated to give12.71 g (95.4%) of free base. A 4.85 g portion of the free base wasconverted to the hydrochloride salt as in Example 1(ethanol-ether/ethereal HCl) thus giving 5.75 g of 3-(1-indolinylmethyl)benzenenmethanamine dihydrochloride, m.p. 160° C. dec.

ANALYSIS: Calculated for C₁₆ H₁₈ N₂.2HCl: 61.74%C; 6.48%H; 9.00%N;Found: 61.54%C; 6.38%H; 8.70%N

EXAMPLE 6 a. 3-(5-Chloro-1-indolyl)benzonitrile

To a stirred solution under nitrogen of 7.58 g (0.050 mole) of5-chloroindole in 50 ml of dimethylsulfoxide (DMSO) was added 1.51 g(0.063 mole) of sodium hydride in portions over a 0.5 hour period. Whenno more bubbles of hydrogen were visible (after 5 hours) a solution of7.63 g (0.063 mole) of 3-fluorobenzonitrile in 10 ml DMSO was addeddropwise over 1 hour. The solution was stirred overnight, and thenheated at 100° C. for 3 hours to complete the reaction. After cooling,the reaction fluids were slowly decanted into 1 liter of ice/water, withgood stirring. This caused the product to separate as chunks of asemi-solid. After 2 hours, the mixture was filtered and the cake washedrepeatedly with water. This material was dissolved in 130 ml of boilingethanol, charcoaled, filtered and allowed to stand overnight (about 16hours). The crystals were collected, washed with ethanol, dried toafford 6.60 g of product (52.4%), having m.p. 116°-120° C.Recrystallization from ethanol gave 3-(5-chloro-1-indolyl)benzonitrilein an overall yield of 42%, m.p. 120°-122° C.

ANALYSIS: Calculated for C₁₅ H₉ ClN₂ : 71.30%C; 3.59%H; 11.09%N; Found:71.29%C; 3.50%H; 11.17%N

b. 3-(5-Chloro-1-indolyl)benzenemethanamine hydrochloride

To a stirred mixture of 1.67 g of lithium aluminum hydride in 100 ml ofdry tetrahydrofuran (THF), kept at 0°-5° C. under nitrogen, was addeddropwise a solution of 5.60 g (0.022 mole) of3-(5-chloro-1-indolyl)benzonitrile of Example 6a in 150 ml of THF. Themixture was stirred 1 hour more at 0° C., 1 hour at room temperature,and then refluxed for 5 hours. After cooling to 0° C., the reaction wasquenched by slow and cautious addition of a solution of 25 ml of waterin 25 ml of THF. The resulting mixture was stirred 1 hour at roomtemperature before filtering to remove the inorganic salts. The filtratewas concentrated to an oily residue which was partitioned between 250 mlof dichloromethane and 250 ml of water. The organic phase was separatedand extracted twice more with water before drying over Na₂ SO₄ andconcentrating to an oil (5.8 g). This was dissolved in 20 ml of absoluteethanol and the stirred solution treated with 100 ml of etherealhydrogen chloride. The salt was collected and found to weigh 5.2 g (81%overall yield) m.p. 195° C.-sinter, 220°-228° C. melting.Recrystallization from boiling ethanol (charcoal) furnished 2.4 g (37%yield) of 3-(5-chloro-1-indolyl)benzenemethanamine hydrochloride, m.p.230°-233° C.

ANALYSIS: Calculated for C₁₅ H₁₃ ClN₂.HCl: 61.45%C; 4.81%H; 9.55%N;Found: 61.33%C; 4.90%H; 9.66%N

EXAMPLE 7 a. 3-(1-Indolyl)benzonitrile

To a stirred solution, under nitrogen, of 17.6 g (0.150 mole) of indolein 100 ml of dry dimethylsulfoxide (DMSO) was added 4.5 g (0.188 mole)of sodium hydride in portions over a 1.5 hour period. When no morebubbles of hydrogen were visible (4-5 hours), there was added dropwise asolution of 22.8 g (0.188 mole) of 3-fluorobenzonitrile in 25 ml of dryDMSO. When the addition was complete (1 hour) the mixture was stirredovernight (about 16 hours) and then 3 hours at 100° C. The cooledmixture was poured into 1.5 liters of a stirred water-ice mixture toprecipitate a semi-solid. The supernatent was poured off and thecoagulated material was washed several times more with water. It wasthen dissolved in 500 ml of dichloromethane, washed twice with dilutebrine, dried over Na₂ SO₄, and concentrated in vacuo to an oil. Thismaterial weighed 32 g (100% yield). A portion was distilled yielding3-(1-indolyl)benzonitrile (160°/0.1 mm) in 75% overall yield. Theproduct was a soft, crystalline material at room temperature, m.p.33°-36° C.

ANALYSIS: Calculated for C₁₅ H₁₀ N₂ : 82.55%C; 4.62%H; Found: 82.29%C;4.56%H

b. 3-(1-Indolyl)benzenemethanamine hydrochloride

To a stirred mixture, kept at 0°-5° C. under nitrogen, of 3.8 g oflithium aluminum hydride in 150 ml of dry tetrahydrofuran was addeddropwise a solution of 10.9 g (0.050 mole) of 3-(1-indolyl)benzonitrileof Example 7a in 50 ml of THF. When the addition was complete (1 hour),the mixture was stirred 1 hour at 0° C., 1 hour at room temperature andfinally refluxed overnight. The mixture was then kept below 5° C. duringcautious addition of a solution of 25 ml H₂ O and 25 ml THF. After theaddition, the mixture was stirred at room temperature for 2 hours,filtered, the cake washed twice with THF, and the combined filtratesconcentrated. The residue was dissolved in 250 ml of dichloromethane andthis solution was washed twice with dilute brine, dried over Na₂ SO₄ andconcentrated to an oil weighing 11.0 g (100%). The oil was dissolved in25 ml of absolute methanol, and then treated in one portion with 50 mlof ether saturated with HCl gas. To the initial solution was addedanother 50 ml of ether. The salt crystallized rapidly and wasimmediately filtered, washed well with ether, and dried to yield 11.6 g(90%) of product, m.p. 189°-191° C. Recrystallization from isopropanolgave 10.0 g (78% overall yield) of pure 3-(1-indolyl)benzenemethanaminehydrochloride, m.p. 190°-192° C.

ANALYSIS: Calculated for C₁₅ H₁₄ N₂.HCl: 69.64%C; 5.84%H; 10.83%N;Found: 69.87%C; 5.71%H; 10.99%N

EXAMPLE 8 a. N-Ethoxycarbonyl-3-(1-indolinyl)benzenemethanamine

A slurry of 10.0 g (39.3 mmole of 3-(1-indolinyl)benzenemethanaminehydrochloride of Example 3b in 120 ml CH₂ Cl₂ was cooled in an ice bathand treated dropwise with a solution of 13.5 ml (95.8 mmole, 2.5equivalents) of triethylamine in 40 ml CH₂ Cl₂. After stirring for tenminutes, the resulting mixture was treated dropwise with a solution of5.5 ml (57.5 mmole, 1.5 equivalents) ethylchloroformate in 40 ml CH₂Cl₂, permitted to warm to room temperature and stir overnight. 100 mlwater were added and, after stirring for 45 minutes, the organic phasewas separated, washed twice with 300 ml 2N HCl, 300 ml H₂ O, 300 mlbrine, dried (Na₂ SO₄), and concentrated to give 10.67 g (93.9%) of anoil. Kugelrohr distillation of a 4.35 g portion afforded 3.45 g ofN-ethoxycarbonyl-3-(1 -indolinyl)benzenemethanamine, bp 200°-208° C./0.1mm.

ANALYSIS: Calculated for C₁₈ H₂₀ N₂ O₂ : 72.95%C; 6.80%H; 9.45%N; Found:72.70%C; 6.75%H; 9.36%N

b. 3-(1-Indolinyl)-N-methyl benzenemethanamine hydrochloride

A solution of 6.8 g (22.9 mmole) ofN-ethoxycarbonyl-3-(1-indolinyl)benzenemethanamine of Example 8a in 45ml distilled THF was added dropwise over 0.5 hours to a rapidly stirred,salt-ice cooled slurry of 3.5 g (91.8 mmole, 4.0 equivalents) LiAlH₄ in100 ml THF. After warming to room temperature, the mixture was heatedunder reflux for 2.25 hours. The ice cold product was treated dropwisewith 3.5 ml water, 7.0 ml 10% NaOH, and 7.0 ml water. The salts werefiltered and washed with 125 ml boiling chloroform. The filtrate wasconcentrated and the residue was dissolved in 100 ml chloroform, washedwith brine (300 ml), dried over Na₂ SO₄, and concentrated to give 5.27 g(96.6%) of free base. The hydrochloride salt was formed in the samemanner as in Example 1 (ether-methylene chloride/ethereal HCl) andrecrystallized from hot isopropanol-ether to afford 3.79 g (60.3%overall) of 3-(1-indolinyl)-N-methyl benzenemethanamine hydrochloride,m.p. 149.0°-150.5° C.

ANALYSIS: Calculated for C₁₆ H₁₈ N₂.HCl: 69.94%C; 6.97%H; 10.19%N;Found: 69.89%C; 6.99%H; 10.02%N

EXAMPLE 9 a. 3-(5-Methoxy-1-indolyl)benzonitrile

To a stirred solution, under nitrogen of 14.7 g (0.100 mole) of5-methoxyindole in 100 ml of dry dimethylsulfoxide (DMSO) was added 3.0g (0.125 mole) of sodium hydride in portions over a 0.5 hour period.When no more bubbles due to liberation of hydrogen gas were observed(after 5 hours), a solution of 15.1 g (0.125 mole) of3-fluorobenzonitrile in 15 ml of DMSO was added dropwise over 0.5 hours.After stirring at room temperature overnight, the reaction was completedby heating at 100° C. for 2 hours. The mixture was cooled and addedslowly to 2 liters of ice-water, with good stirring. This caused theproduct to separate as finely divided particles. These were filtered andthe cake dissolved in 250 ml of dichloromethane. This solution wasextracted twice with brine, dried over Na₂ SO₄, and concentrated invacuo to an oil (22.5 g) which began to crystallize. This was boiled andtriturated with 25 ml ethanol to provide 18.3 g (74%) of a solid, m.p.106°-112° C. Recrystallization from ethanol furnished 14.7 g (59%overall yield) of product, m.p. 110°-113° C. A sample was recrystallizedagain from ethanol to yield 3-(5-methoxy-1-indolyl)benzonitrile, m.p.113°-115° C.

ANALYSIS: Calculated for C₁₆ H₁₂ N₂ O: 77.40%C; 4.87%H; 11.28%N; Found:77.40%C; 5.01%H; 11.40%N

b. 3-(5-Methoxy-1-indolyl)benzenemethanamine hydrochloride

To a stirred mixture of 2.28 g of lithium aluminum hydride in 100 ml ofdry tetrahydrofuran (THF), kept at 0° under nitrogen, was added dropwisea solution of 7.45 g (0.030 mole) of 3-(5-methoxy-1-indolyl)benzonitrileof Example 9a in 40 ml of THF. When the addition was complete (1 hour)the mixture was stirred 1 hour longer at 0° C., 1 hour at roomtemperature and then refluxed for 5 hours. After cooling back down to 0°C., the reaction was quenched by slow and cautious addition of asolution of 20 ml of water in 20 ml of THF. The resulting mixture wasstirred 1 hour at room temperature before filtering to remove salts. Thefiltrate was concentrated to a residue which was partitioned between 200ml of dichloromethane and 200 ml of water. The organic phase wasseparated and extracted twice with dilute brine before drying over Na₂SO₄. After concentration of the organic phase in vacuo there wasobtained 7.2 g (95%) of oil. The hydrochloride salt of this material wasprepared in the following manner. The oil was dissolved in 25 ml ofmethanol, and with good stirring, 100 ml of ethereal hydrogen chloridewas added. The salt crystallized and was collected, washed well withether and dried to yield 5.5 g (63%), m.p. 205°-209° C. This wasrecrystallized from 55 ml of hot ethanol (charcoal) to afford 2.3 g (27%overall yield) of 3-(5-methoxy-1-indolyl)benzenemethanaminehydrochloride, m.p. 209°-212° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₂ O.HCl: 66.55%C; 5.93%H; 9.70%N;Found: 66.43%C; 5.76%H; 9.71%N

EXAMPLE 10 a. 3-(5-Methoxy-1-indolinyl)benzonitrile

A solution of 4.0 g (16.1 mmole) of 3-(5-methoxy-1-indolyl)benzonitrileof Example 9a in 160 ml glacial acetic acid under nitrogen at 15°-20° C.was treated with 3.14 g (49.9 mmole, 3.1 equivalents) sodiumcyanoborohydride. The reaction mixture was permitted to warm to roomtemperature and stir overnight (about 16 hours). The resulting solutionwas poured over ice (200 ml), made basic using 50% NaOH (165 ml) andextracted with chloroform (350 ml total). The combined organic extractswere washed with water (400 ml), brine (400 ml), dried over Na₂ SO₄, andconcentrated to give 3.90 g (96.8%) of the crude indoline as an oil.Crystallization from hot ethyl acetate-hexane afforded 1.87 g (46.4%overall) of 3-(5-methoxy-1-indolinyl)benzonitrile, m.p. 92.5°-93.5° C.

ANALYSIS: Calculated for C₁₆ H₁₄ N₂ O: 76.78%C; 5.64%H; 11.19%N; Found:76.62%C; 5.80%H; 11.24%N

b. 3-(5-Methoxy-1-indolinyl)benzenemethanamine hydrochloride

A solution of 2.84 g (11.3 mmole) of3-(5-methoxy-1-indolinyl)benzonitrile of Example 10a in 35 ml distilledTHF was added dropwise over 1.25 hours to a rapidly stirred ice coldslurry of 1.72 g (45.4 mmole, 4.0 equivalents) LiAlH₄ in 50 ml distilledTHF under nitrogen. After warming to room temperature, the mixture washeated under reflux for 2.25 hours, cooled in an ice bath, and quenchedby dropwise addition of 2 ml water, 3 ml 10% NaOH, and 5 ml water. Thesalts were filtered and washed with boiling methylene chloride (200-259ml). The filtrate was concentrated and the residue was dissolved inmethylene chloride (150 ml) and washed with brine (250 ml), dried overNa₂ SO₄, and concentrated to give 2.71 g (94.3%) of crude free base.Conversion to the hydrochloride salt (ether/ethereal HCl) as in Example1, and recrystallization from isopropanol-ether afforded 2.10 g (63.9%)of 3-(5-methoxy-1-indolinyl)benzenemethanamine hydrochloride, m.p.195.5° C. dec.

ANALYSIS: Calculated for C₁₆ H₁₈ N₂ O.HCl: 66.09%C; 6.59%H; 9.63%N;Found: 66.20%C; 6.61%H; 9.56%N

EXAMPLE 11 N-Cyclopropylcarbonyl-3-(1-indolinyl)benzenemethanamine

A rapidly stirred ice cold slurry of 16.59 g (63.62 mmole) of3-(1-indolinyl)benzenemethanamine hydrochloride of Example 3b in 300 mlCH₂ Cl₂ was treated dropwise over 15 minutes with a solution of 20.6 ml(146.33 mmole, 2.3 equivalents) triethylamine in 25 ml CH₂ Cl₂. Afterstirring for 10 minutes, a solution of 6.9 ml (76,34 mmole, 1.2equivalents) cyclopropanecarboxylic acid chloride in 20 ml CH₂ Cl₂ wasadded dropwise over 27 minutes. After stirring for 2 hours at roomtemperature, 75 ml water was added and the organic phase was separatedand washed twice with 2N HCl (300 ml), once with 5% NaOH (400 ml), oncewith brine (400 ml), dried over Na₂ SO₄, and concentrated to give 18.8 gof crude amide. Column chromatography of a 4.93 g portion on silica gelusing ether-hexane afforded 4.03 g (81.7%) ofN-cyclopropylcarbonyl-3-(1-indolinyl)benzenemethanamine oil.

ANALYSIS: Calculated for C₁₉ H₂₀ N₂ O: 78.05%C; 6.90%H; 9.58%N; Found:78.00%C; 6.67%H; 9.69%N

EXAMPLE 12 3-(1-Indolinyl)-N-phenylacetyl benzenemethanamine

A rapidly stirred ice cold slurry of 16.41 g (62.93 mmole)3-(1-indolinyl)benzenemethanamine hydrochloride of Example 3b in 300 mlCH₂ Cl₂ was treated dropwise over 16 minutes with a solution of 20.4 ml(144.74 mmole, 2.3 equivalents) triethylamine in 25 ml CH₂ Cl₂. Asolution of 10.0 ml (75.5 mmole, 1.2 equivalents) phenylacetyl chloridein 20 ml CH₂ Cl₂ was then added dropwise over 17 minutes. After stirringfor 2 hours at room temperature, 75 ml water was added and the organicphase was separated and washed twice with 2N HCl, once with 5% NaOH,twice with brine, dried over Na₂ SO₄, and concentrated to give 23.98 gof crude amide (bp>250° C./0.1 mm.). A 5.61 g portion waschromatographed on 90 g of silica gel using hexane-methylene chloride togive 2.89 g (51.5%) of 3-(1-indolinyl)-N-phenylacetylbenzenemethanamine.

ANALYSIS: Calculated for C₂₃ H₂₂ N₂ O: 80.67%C; 6.48%H; 8.18%N; Found:80.46%C; 6.45%H; 8.00%N

EXAMPLE 13 N-Cyclopropylmethyl-3-(1-indolinyl)benzenemethanaminehydrochloride

A solution of 10.29 g (36.19 mmole) ofN-cyclopropylcarbonyl-3-(1-indolinyl)benzenemethanamine of Example 11 in50 ml THF was added dropwise over 50 minutes to an ice cold rapidlystirred slurry of 1.00 g (26.4 mmole, 0.75 equiv.) LiAlH₄ in 50 ml THFunder nitrogen. After heating under reflux for 23 hours, considerablestarting material was evident by thin layer chromatography (TLC) (silicagel 5% methanol in ether). The reaction mixture was cooled in an icebath and treated with an ice cold slurry of 1.0 g (0.75 equivalents)LiAlH₄ in 40 ml THF. After heating under reflux for five hours anadditional 2.0 g (1.5 equivalents) LiAlH₄ was added as a cold slurry inTHF. Total LiAlH₄ charge was 4.0 g (105.4 mmole, 3.0 equivalents); totalreflux time was 30 hours. Finally, the ice cold reaction mixture wastreated dropwise with 4 ml water, 8 ml 10% NaOH, and 8 ml H₂ O. Thesalts were filtered, washed with boiling methylene chloride (400 ml),and the filtrate was concentrated. The residue was dissolved inmethylene chloride (100 ml), washed with brine (250 ml), dried over Na₂SO₄ and concentrated to give 8.44 g (86.2%) of crude free base.Conversion to the hydrochloride salt (ether/ethereal HCl), utilizing theprocedure as in Example 1 and recrystallization from hot isopropanolyielded 4.00 g (36.1% overall) ofN-cyclopropylmethyl-3-(1-indolinyl)benzenemethanamine hydrochloride,m.p. 156.5°-158.0° C.

ANALYSIS: Calculated for C₁₉ H₂₂ N₂.HCl: 72.48%C; 7.36%H; 8.90%N; Found:72.34%C; 7.25%H; 8.72%N

EXAMPLE 14 3-(1-Indolinyl)-N-(2-phenylethyl)benzenemethanaminehydrochloride

A solution of 15.53 g (45.35 mmole) of3-(1-indolinyl)-N-phenylacetylbenzenemethanamine of Example 12 in 65 mldistilled THF was added dropwise over 30 minutes to an ice-salt cooled,rapidly stirred slurry of 10.44 g (275.1 mmole, 6.07 equivalents) LiAlH₄in 275 ml distilled THF under nitrogen. After warming to roomtemperature and stirring for 2 hours, the reaction mixture was heatedunder reflux for 19 hours and then quenched at 0° C. with 20 ml icewater-THF (1:1), 10 ml 10% NaOH, and 30 ml water. The salts werefiltered, washed with CHCl₃ and the filtrate was concentrated. Theresidue was dissolved in CHCl₃, washed with brine, dried over Na₂ SO₄,and concentrated to give 11.70 g (78.6%) of crude free base. Conversionto the HCl salt (ether/ethereal HCl) using the procedure of Example 1gave 11.43 g (69.1%). Recrystallization from hot absolute ethanol gave2.88 g (17.4% overall) of3-(1-indolinyl)-N-(2-phenylethyl)benzenemethanamine hydrochloride, m.p.188°-190° C.

ANALYSIS: Calculated for C₂₃ H₂₁ N₂.HCl: 75.70%C; 6.90%H; 7.86%N; Found:75.86%C; 6.60%H; 7.61%N

EXAMPLE 15 N-Ethoxycarbonyl-3-(1-indolinyl)-N-methylbenzenemethanamine

An ice cold rapidly stirred solution of 7.73 g (28.18 mmole) of3-(1-indolinyl)-N-methyl benzenemethanamine hydrochloride of Example 8bin 150 ml CH₂ Cl₂ was treated dropwise with a solution of 9.9 ml (70.45mmole, 2.5 equivalents) of triethylamine in 10 ml CH₂ Cl₂. Afterstirring for three minutes, a solution of 4.0 ml (42.27 mmole, 1.5equivalents) ethyl chloroformate in 10 ml CH₂ Cl₂ was added dropwise. Atthe end of the addition the reaction mixture was permitted to warm toroom temperature, stirred for 1 hour and stand about 64 hours. Water(200 ml) was added and the organic layer was separated and washed with2N HCl (200 ml), water (300 ml), brine (300 ml), dried (Na₂ SO₄), andconcentrated to give 7.64 g (87.3%) of crude product. Chromatography onsilica gel (85 g) using ether-methylene chloride afforded 6.73 g (76.9%overall) of an oil ofN-ethoxycarbonyl-3-(1-indolinyl)-N-methylbenzenemethanamine, bp>240°C./0.1 mm.

ANALYSIS: Calculated for C₁₉ H₂₂ N₂ O₂ : 73.52%C; 7.14%H; 9.02%N; Found:73.52%C; 7.05%H; 8.74%N

EXAMPLE 16 N,N-Dimethyl-3-(1-indolinyl)benzenemethanamine hydrochloride

A solution of 4.17 g (13.4 mmole) ofN-ethoxycarbonyl-3-(1-indolinyl)-N-methylbenzenemethanamine of Example15 in 20 ml distilled THF was added dropwise over 30 minutes to an icecold rapidly stirred slurry of 2.04 g (53.7 mmole, 4.0 equivalents) ofLiAlH₄ in 55 ml distilled THF under nitrogen. After heating under refluxfor 2 hours, the reaction mixture was cooled in an ice bath andcarefully treated dropwise with 2 ml water, 2 ml 10% NaOH, and 6 mlwater. The salts were filtered, washed with hot methylene chloride (300ml) and the filtrate was concentrated. The residue was dissolved inCHCl₃ (75 ml), washed with brine, dried over Na₂ SO₄ and concentrated togive 3.26 g (96.4%) of the crude free base as an oil. Conversion to thehydrochloride salt (ether/ethereal HCl), utilizing the procedure ofExample 1, and recrystallization from hot methanol-isopropanol afforded2.82 g (72.9% overall) of N,N-dimethyl-3-(1-indolinyl)benzenemethanaminehydrochloride, m.p. 203°-204° C.

ANALYSIS: Calculated for C₁₇ H₂₀ N₂.HCl: 70.70%C; 7.33%H; 9.70%N; Found:70.42%C; 7.53%H; 9.45%N

EXAMPLE 17 a. α-(5-Chloro-1-indolinyl)-m-tolunitrile

A solution of 5.17 g (26.5 mmole)α-bromo-m-tolunitrile in 45 ml sievedried dimethylformamide (DMF) was added dropwise over 20 minutes to anice cold, rapidly stirred slurry of 4.07 g (26.5 mmole) 5-chloroindolineand 3.66 g (26.5 mmole) potassium carbonate in 25 ml sieve dried DMFunder nitrogen. After warming to room temperature and stirring for 5hours, the solvent was removed under high vacuum (50°-60° C.). Theresidue was partitioned between chloroform and water and the organicphase was separated, washed with water, brine, dried over Na₂ SO₄, andconcentrated to give 6.95 g (97.6%) of product. Recrystallization fromhot absolute ethanol afforded 5.10 g (71.6% overall) ofα-(5-chloro-1-indolinyl)-m-tolunitrile, m.p. 73.5°-75.5° C.

ANALYSIS: Calculated for C₁₆ H₁₃ ClN₂ : 71.51%C; 4.88%H; 13.19%Cl;10.42%N; Found: 71.45%C; 4.91%H; 13.00%Cl; 10.49%N

b. 3-(5-Chloro-1-indolinylmethyl)benzenemethanamine fumarate

A solution of 4.41 g (16.4 mmole) ofα-(5-chloro-1-indolinyl)-m-tolunitrile of Example 17a in 30 ml distilledTHF was added dropwise over 30 minutes to a rapidly stirred ice coldslurry of 2.49 g (65.6 mmole, 4.0 equivalents) LiAlH₄ in 65 ml distilledTHF under nitrogen. After warming to room temperature, the mixture washeated under reflux for 2.75 hours, cooled in an ice bath, and quenchedby dropwise addition of 2.5 ml water, 2.5 ml 10% NaOH, and 7.5 ml water.The salts were filtered and washed with 250 ml boiling methylenechloride. The filtrate was concentrated and the residue was dissolved inmethylene chloride (100 ml), washed with brine (250 ml), dried over K₂CO₃, and concentrated to give 4.29 g (95.9%) of crude free base. Thefree base (4.23 g, 15.5 mmole) was dissolved in 30 ml absolute ethanoland added to a warm solution of 1.80 g (15.5 mmole) fumaric acid in 80ml absolute ethanol. The fumarate salt slowly crystallized upon coolingto room temperature, thus affording 5.12 g (84.9%) of3-(5-chloro-1-indolinylmethyl)benzenemethanamine fumarate, m.p. 178° C.,dec.

ANALYSIS: Calculated for C₁₆ H₁₇ N₂ Cl.C₄ H₄ O₄ : 61.78%C; 5.44%H;9.12%Cl; 7.20%N; Found: 61.82%C; 5.45%H; 9.10%Cl; 7.23%N

EXAMPLE 18 a. 3-(5-Benzyloxy-1-indolyl)benzonitrile

To a rapidly stirred solution of 15.0 g (67.2 mmole) 5-benzyloxyindolein 75 ml sieve dried dimethylsulfoxide (DMSO) under nitrogen at roomtemperature was added in one portion 2.02 g (84 mmole, 1.25 equivalents)of 99% NaH. After stirring for 4.5 hours at room temperature, a solutionof 10.17 g (84 mmole, 1.25 equivalents) 3-fluorobenzonitrile in 20 mlsieve dried DMSO was added dropwise over six minutes. The reactionmixture was permitted to stir overnight at room temperature and then washeated at 80°-90° C. for 2 hours. The cooled product was poured onto ice(100 ml) and extracted with chloroform. In order to clear an emulsionthat formed at this point, a filtration through a pad of celite wasnecessary. The organic portion was washed successively with water, 2NHCl, brine, dried over Na₂ SO₄ and concentrated to give 22.01 g ofproduct. Crystallization from hot glacial acetic acid afforded 19.46 gof a low melting (36°-40° C.) solvated product(nitrile:solvent=1:1-2.0). A 4.8 g portion of the recrystallizedmaterial was chromatographed on silica gel (ether-hexane) to give 3.0 gof 3-(5-benzyloxy-1-indolyl)benzonitrile.

ANALYSIS: Calculated for C₂₂ H₁₆ N₂ O: 81.46%C; 4.97%H; 8.64%N; Found:81.18%C; 5.03%H; 8.50%N

b. 3-(5-Benzyloxy-1-indolinyl)benzonitrile

A cooled (17°-19° C.), rapidly stirred slurry of 16.2 g (49.9 mmole) of3-(5-benzyloxy-1-indolyl)benzonitrile of Example 18a in 200 ml glacialacetic acid under nitrogen was treated portionwise with 9.73 g (3.1equivalents, 154.8 mmole) sodium cyanoborohydride. After warming to roomtemperature and stirring overnight (about 16 hours) under nitrogen, thereaction mixture was poured onto 200 ml ice, carefully made basic using50% NaOH, and extracted with methylene chloride. The organic portion waswashed with water, brine, dried over Na₂ SO₄, and concentrated to give15.45 g (94.8%) of product. A 5.0 g portion was chromatographed onsilica gel using ether-hexane to give 3.85 g (73% overall) of3-(5-benzyloxy-1-indolinyl)benzonitrile, m.p. 101.5°-103.5° C. Ananalytical sample was prepared by recrystallization from ethylacetate-hexane, m.p. 101° C.

ANALYSIS: Calculated for C₂₂ H₁₈ N₂ O: 80.96%C; 5.56%H; 8.58%n; Found:80.80%C; 5.59%H; 8.54%N

c. N-Acetyl-3-(5-benzyloxy-1-indolinyl)benzenemethanamine

A solution of 1.52 g (4.7 mmole) of3-(5-benzyloxy-1-indolinyl)benzonitrile of Example 18b in 60 ml aceticanhydride over 0.2 g Raney Nickel (#28 finely divided) and 0.76 g (9.3mmole, 2 equivalents) sodium acetate was shaken at 50° C. under 50 psiof hydrogen until gas uptake had ceased and TLC analysis showed thereduction to be complete. The catalyst was filtered on a pad of celiteand the filtrate was partitioned between chloroform (40 ml) and water(400 ml) and the combined organic portions were washed twice with water(600 ml), aqueous NaHCO₃ (two 600 ml portions) and brine, dried over Na₂SO₄, and concentrated to give an oil. Chromatography on silica gel (80g) using 1-5% methanol in ether afforded 1.31 g (86.8%) ofN-Acetyl-3-(5-benzyloxy-1-indolinyl)benzenemethanamine as an oil.

ANALYSIS: Calculated for C₂₄ H₂₄ N₂ O₂ : 77.39%C; 6.50%H; 7.52%N; Found:77.15%C; 6.54%H; 7.39%N

EXAMPLE 19 3-(5-Benzyloxy-1-indolinyl)benzenemethanamine hydrochloride

A solution of 2.82 g (8.64 mmole) of3-(5-benzyloxy-1-indolinyl)benzonitrile of Example 18b in 20-25 mldistilled THF was added dropwise over twelve minutes to a rapidlystirred ice cold slurry of 1.31 g (34.56 mmole, 4.0 equivalents) LiAlH₄in 35 ml distilled THF under nitrogen. After warming to roomtemperature, the mixture was heated under reflux for 2 hours, permittedto cool to room temperature, placed in an ice bath, and treated dropwisewith 1.3 ml water, 1.3 ml 10% NaOH and 3.9 ml water. The salts werefiltered and washed with 200 ml boiling methylene chloride. The filtratewas concentrated and the residue was dissolved in 100 ml CH₂ Cl₂, washedwith brine, dried over Na₂ SO₄ and concentrated to give 2.37 g (83%) ofcrude free base. Conversion to the hydrochloride salt (dryether-isopropanol/ethereal HCl) as in Example 1 and recrystallizationfrom isopropanol containing 10-20% methanol gave 1.89 g (59.6%) of3-(5-benzyloxy-1-indolinyl)benzenemethanamine hydrochloride, m.p.177°-180° C.

ANALYSIS: Calculated for C₂₂ H₂₂ N₂ O.HCl: 72.02%C; 6.32%H; 7.64%N;Found: 72.18%C; 6.24%H; 7.57%N

EXAMPLE 20 a. 3-(1-Indolinyl)benzoic acid

A mixture of 47.7 g (5.3 equivalents) KOH pellets and 30.0 g (0.136mole) 3-(1-indolinyl)benzonitrile of Example 3a in 270 ml ethyleneglycol was heated at 180° for 6 hours (the mixture became homogeneous at150°). After cooling to room temperature, the product was poured onto amixture of 400 ml ice/85 ml (ca. 1 mole) concentrated HCl and extractedwith CHCl₃ (850 ml total). The organic portion was washed with water(750 ml), brine (600 ml), dried over Na₂ SO₄, and concentrated to give35.0 g of crude acid (theory=32.6 g).

Recrystallization from chloroform-toluene gave 19.43 g (59.7%), m.p.166°-168.5° C. A second recrystallization of a 5.1 g portion gave 4.28 gof 3-(1-indolinyl)benzoic acid, m.p. 168°-170.5° C.

ANALYSIS: Calculated for C₁₅ H₁₃ NO₂ : 75.30%C; 5.48%H; 5.85%N; Found:75.12%C; 5.52%H; 5.83%N

b. 3-(1-Indolinyl)benzenemethanol

A solution of 16.10 g (67.3 mmole) of 3-(1-indolinyl)benzoic acid ofExample 20a in 75 ml dry THF was added dropwise over seven minutes to arapidly stirred, ice cold slurry of 2.55 g (67.3 mmole) lithium aluminumhydride in 50 ml dry THF. The ice bath was removed at the end of theaddition and, after warming to room temperature, the reaction mixturewas heated at reflux for 1 hour. The product was cooled to 0°-5° C. andtreated dropwise with 3 ml water, 3 ml 10% aqueous NaOH and 9 ml water.The salts were filtered, washed 3 times with boiling chloroform (100 mltotal), and the filtrate was concentrated. The residue was dissolved inchloroform, washed with brine, dried over Na₂ SO₄, concentrated, anddried under high vacuum to give 14.42 g (95.1%) of an oil. Kugelrohrdistillation of a 6.50 g portion afforded 5.75 g (83% overall yield) of3-(1-indolinyl) benzenemethanol, b.p. 204°-208° C./0.13 mm.

ANALYSIS: Calculated for C₁₅ H₁₅ NO: 79.97%C; 6.71%H; 6.22%N; Found:79.88%C; 6.43%H; 6.01%N

c. 3-(1-Indolinyl)benzenemethanesulfonic acid methyl ester

A stirred solution of 8.11 g (36 mmole) of3-(1-indolinyl)benzenemethanol of Example 20b and 7.6 ml (54 mmole) oftriethylamine in 35 ml of methylene chloride (CH₂ Cl₂) was cooled to 0°C. and then treated dropwise with a solution of 3.1 ml (40 mmole) ofmethanesulfonyl chloride in 35 ml of CH₂ Cl₂. Ten minutes after theaddition, 150 ml of water was added. The organic layer was separated,washed twice with 150 ml of cold 2N-HCl, then with 150 ml of saturatedNaHCO₃, with 150 ml of brine, dried over Na₂ SO₄ and concentrated invacuo. This left 10.3 g (93.9% yield) of3-(1-indolinyl)benzenemethanesulfonic acid methyl ester as an oil.

d. 3-(1-Indolinyl)benzeneacetonitrile

A mixture of 10.2 g (ca. 33.8 mmole) of3-(1-indolinyl)benzenemethanesulfonic acid methyl ester of Example 20cand 4.97 g (101.4 mmole, 3.0 equiv.) sodium cyanide in 200 ml sievedried DMF was heated at 60°-70° C. for 50 minutes. The product wasconcentrated under high vacuum at 50°-60° C. and the residue waspartitioned between chloroform (200 ml) and water (200 ml). The organicportion was washed twice with 200 ml water, 200 ml brine, dried over Na₂SO₄ and concentrated under vacuum to give 6.39 g (80.7%) of product.Kugelrohr distillation of a 0.8 g sample gave 0.6 g of an oil of3-(1-indolinyl)benzeneacetonitrile, b.p. 189°-192° C./0.15 mm.

ANALYSIS: Calculated for C₁₆ H₁₄ N₂ : 82.02%C; 6.02%H; 11.96%N; Found:81.85%C; 5.93%H; 12.14%N

e. N-Acetyl-2-[3-(1-indolinyl)]benzeneetthanamine

A sample of 0.37 g (wet wt.) #28 finely divided Raney Nickel catalystwas carefully washed thrice with absolute ethanol and thrice with aceticanhydride. The moist catalyst was then added to a solution of 2.0 g(8.54 mmoles) of 3-(1-indolinyl)benzeneacetonitrile of Example 20d in 50ml acetic anhydride over 1.05 g (1.5 equivalents, 12.81 mmole) sodiumacetate (anhydrous powder) in a 500 ml Parr bottle. The mixture wasshaken at 50° C. under 50 psi H₂ until gas uptake ceased and TLCanalysis showed no starting material was present. The catalyst wasfiltered on a pad of celite and the filtrate was concentrated to give2.37 g (100%) of the product as an oil. Chromatography on 45 g of silicagel using increasingly polar mixtures of ether-hexane thenmethanol-ether afforded 1.62 g (67.8% overall) ofN-acetyl-2-[3-(1-indolinyl)]benzeneethanamine as an oil.

ANALYSIS: Calculated for C₁₈ H₂₀ N₂ O: 77.11%C; 7.19%H; 9.99%N; Found:77.38%C; 7.04%H; 9.96%N

f. 3-(1-Indolinyl)-2-benzeneethanamine.1/2 fumarate

A mixture of 5.97 g (21.29 mmole) ofN-acetyl-2-[3-(1-indolinyl)]benzeneethanamine of Example 20e, 4.78 g (4equivalents, 85.17 mmole) 85% KOH pellets, 5 ml water, and 85 mlethylene glycol was heated at 160°-180° C. for 4 hours. The product waspoured onto ice and extracted three times with chloroform (200 mltotal). The combined organic extracts were washed with water (250 ml),brine (250 ml), dried (Na₂ SO₄) and concentrated to give 4.89 g (96.4%)of the crude free base as an oil. A warm solution of fumaric acid (2.38g, 20.5 mmole) in absolute ethanol (35 ml) was treated with a filteredsolution of the free base (4.89 g, 20.5 mmole) in absolute ethanol (30ml). The pure fumarate salt crystallized slowly upon standing overnightin the cold. The crystals were collected, washed with absolute ethanol,then with dry ether and dried to give 4.51 g (74.2%) of3-(1-indolinyl)-2-benzeneethanamine.1/2 fumarate, m.p. 191°-193° C.

ANALYSIS: Calculated for C₁₆ H₁₈ N₂.1/2C₄ H₄ O₄ : 72.95%C; 6.80%H;9.45%N; Found: 73.09%C; 6.40%H; 9.25%N

EXAMPLE 21 3-(1-Indolinyl)-α-methylbenzenemethanamine hydrochloride

A solution of 5.07 g (23.02 mmole) of 3-(1-indolinyl)benzonitrile ofExample 3a in 50 ml distilled THF was added dropwise over 36 minutes toan ice cold stirred solution of 2.74M (16.8 ml, 2.0 equivalents, 45mmole) methyl magnesium chloride in tetrahydrofuran (THF) undernitrogen. At the end of the addition the product was permitted to warmto room temperature. After heated at 60° C. for 2 hours, the mixture wascooled in an ice bath and treated with an ice cold slurry of 1.75 g (46mmole) LiAlH₄ in 75 ml distilled THF. Upon warming to room temperature,the reaction mixture was heated under reflux for 1 hour, cooled in anice bath, treated dropwise with 2 ml ice water, 2 ml 10% NaOH, and 6 mlwater. The salts were filtered, washed four times with boiling methylenechloride (350 ml total) and the filtrate was concentrated. The residuewas dissolved in chloroform, washed with brine, dried over Na₂ SO₄ andconcentrated to give 4.83 g (88.0%) of free base as an oil. Conversionof a 6.7 g sample of free base (from two separate preparations) to thehydrochloride salt (ether/ethanol HCl) as in Example 1 andrecrystallization from ethanol-ethyl acetate afforded 3.18 g (36%) of3-(1-indolinyl)-α-methylbenzenemethanamine hydrochloride, m.p.223.0°-225.5° C.

ANALYSIS: Calculated for C₁₆ H₁₈ N₂.HCl: 69.93%C; 6.97%H; 10.19%N;Found: 69.77%C; 6.99%H; 10.02%N

EXAMPLE 22 3-(1-Indolinyl)-α-phenylbenzenemethanamine hydrochloride

A solution of 3.0 g (13.6 mmole) of 3-(1-indolinyl) benzonitrile ofExample 3a in 15 ml THF was added dropwise over 17 minutes to an icecooled, magnetically stirred solution of 2.8M (10-11 ml, ca. 2equivalents, 27.2 mmole) phenyl magnesium bromide in ether. The mixturewas permitted to warm to room temperature, and then heated at 50°-60° C.for 1.75 hours. After cooling to 0°-5° C., the stirred product wastreated with an ice cold slurry of 1.03 g (27.2 mmole) LiAlH₄ in 15 mlTHF. The resulting slurry was heated at 60° C. for 2.5 hours, cooled to0°-5° C., and treated dropwise with 1 ml water, 1 ml 10% NaOH and 5 mlwater. The salts were filtered, washed with boiling methylene chlorideand the filtrate was concentrated. The residue was dissolved inchloroform, washed with brine, dried over Na₂ SO₄, and concentrated togive 3.89 g (95.1%) of the crude free base as an oil. Conversion to thehydrochloride salt (ether/ethereal HCl) as in Example 1, andrecrystallization from ethanol-ethyl acetate afforded 2.43 g (53.0%) of3-(1-indolinyl)-α-phenylbenzenemethanamine hydrochloride, m.p.244.0°-245.5° C.

ANALYSIS: Calculated for C₂₁ H₂₀ N₂.HCl: 74.88%C; 6.28%H; 8.32%N; Found:74.61%C; 6.36%H; 8.34%N

EXAMPLE 23 a. α-(5-Methoxy-1-indolinyl)-m-tolunitrile

An ice cold slurry of 5.89 g (42.6 mmole) of K₂ CO₃ and 5.3 g (35.5mmole) of 5-methoxyindoline in 55 ml of DMF was treated dropwise with asolution of 7.28 g (37.3 mmole) of α-bromo-m-tolunitrile in 50 ml ofDMF. After stirring for 1 hour at room temperature, the reaction mixturewas concentrated under high vacuum. The residue was partitioned betweenmethylene chloride (250 ml) and water (250 ml). The organic layer wasseparated, washed with 5% NaOH (300 ml), brine (300 ml), dried over Na₂SO₄ and concentrated under vacuum to yield 9.28 g (98.9% yield) ofα-(5-methoxy-1-indolinyl)-m-tolunitrile.

b. 3-(5-Methoxy-1-indolinylmethyl)benzenemethanamine dihydrochloride

A solution of 4.85 g (18.35 mmole) ofα-(5-methoxy-1-indolinyl)-m-tolunitrile of Example 23a in 45 ml THF wasadded dropwise over 40 minutes to an ice cold, rapidly stirred slurry of2.79 g (73.4 mmole, 4 equivalents) LiAlH₄ in THF under nitrogen. Afterheating under reflux for 1 hour the reaction mixture was cooled to 0°-5°C. and treated dropwise with 3 ml ice water, 3 ml 10% NaOH and 8 mlwater. The salts were filtered, washed twice with warm chloroform (250ml total), and the filtrate was concentrated. The residue was dissolvedin chloroform, washed with brine, dried over Na₂ SO₄, and concentratedto give 4.47 g (90.8%) of crude free base. Conversion to thehydrochloride salt (ether/ethereal HCl) as in Example 1 afforded 4.84 g(77.3%). Recrystallization from n-butanol gave 3.62 g (57.9% overall) of3-(5-methoxy-1-indolinylmethyl)benzenemethanamine dihydrochloride, m.p.167° C., dec.

ANALYSIS: Calculated for C₁₇ H₂₀ N₂ O.2HCl: 59.83%C; 6.50%H; 8.21%N;Found: 59.84%C; 6.78%H; 8.04%N

We claim:
 1. A compound having the formula ##STR27## where X ishydrogen, halogen, lower alkoxy, Ar lower alkoxy of the formula##STR28## the alkylene moiety having 1 to 5 carbons and m, n and p areindependently an integer of 0 or
 1. 2. The compound as defined in claim1 where p is
 0. 3. The compound as defined in claim 2 which is2-(1-indolinyl)benzonitrile.
 4. The compound as defined in claim 2 whichis 4-(1-indolinyl)benzonitrile.
 5. The compound as defined in claim 2which is 3-(1-indolinyl)benzonitrile.
 6. The compound as defined inclaim 2 which is 3-(5-chloro-1-indolinyl)benzonitrile.
 7. The compoundas defined in claim 2 which is α-(1-indolinyl)-m-tolunitrile.
 8. Thecompound as defined in claim 2 which is3-(5-methoxy-1-indolinyl)benzonitrile.
 9. The ciompound as defined inclaim 2 which is 3-(5-benzyloxy-1-indolinyl)benzonitrile.
 10. Thecompound as defined in claim 1 where p is
 1. 11. The compound as definedin claim 10 which is 3-(5-chloro-1-indolyl)benzonitrile.
 12. Thecompound as defined in claim 11 which is 3-(1-indolyl)benzonitrile. 13.The compound as defined in claim 11 which is3-(5-methoxy-1-indolyl)benzonitrile.
 14. The compound as defined inclaim 11 which is 3-(5-benzyloxy-1-indolyl)benzonitrile.
 15. Thecompound as defined in claim 1 where m is
 1. 16. The compound as definedin claim 15 which is α-(5-chloro-1-indolinyl)-m-tolunitrile.
 17. Thecompound as defined in claim 1 where n is
 1. 18. The compound as definedin claim 17 which is 3-(1-indolinyl)benzeneacetonitrile.
 19. A compoundhaving the formula ##STR29## where X is hydrogen, halogen, lower alkoxy,Ar lower alkoxy of the formula ##STR30## and m and p are independentlyan integer of 0 or 1 and R₄ is lower alkyl or phenyl.